Benzene exposure promotes neuroinflammation and metabolic dysregulation
接触苯会促进神经炎症和代谢失调
基本信息
- 批准号:10597556
- 负责人:
- 金额:$ 38.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-01 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAffectAgeAir PollutionAstrocytesAttentionBenzeneBenzene ExposureCellsChronicDetergentsDevelopmentDoseEnergy MetabolismEnvironmentEnvironmental ExposureEnvironmental and Occupational ExposureEtiologyExposure toFoodFutureGeneral PopulationGeneticGlucoseGoalsHealthHealth PolicyHistologyHomeostasisHumanHyperglycemiaHypothalamic structureImmuneImpairmentIn Situ HybridizationIn VitroIndividualInflammationInflammatoryInflammatory ResponseInsulinInsulin ResistanceInterventionKnockout MiceLeptinLinkLiteratureLoxP-flanked alleleMediatingMeta-AnalysisMetabolicMetabolic DiseasesMetabolic dysfunctionMetabolismMicrogliaModelingModernizationMolecularMorphologyMusNeurogliaNon-Insulin-Dependent Diabetes MellitusObesityOccupationalOutcomeOxidative Stress InductionPaintPathologyPathway interactionsPeripheralPhysiologicalPollutionPredispositionPregnant WomenPublic HealthPublishingRegulationResearchRiskRodentRoleShapesSignal PathwaySignal TransductionSocietiesSystemTestingTimeTissuesTobacco smokeUnderrepresented MinorityWaterWorkbiological adaptation to stressblood glucose regulationconditional knockoutcostdesigne-cigarette aerosolsendoplasmic reticulum stressexhaustexposure routeexposure to cigarette smokeglial activationglucose metabolismglucose monitorhuman modelimmunological statusin vivoinsightinsulin signalinginsulin tolerancemalemouse modelneuroinflammationnew therapeutic targetnovelpreventresponsesystemic inflammatory responseurban areaurinaryvolatile organic compoundyoung adult
项目摘要
ABSTRACT
Benzene is a prominent volatile organic compound (VOCs) that is present in water, food, paint,
detergents, vehicle exhaust, tobacco smoke, and e-cigarette vapors. Exposure to low doses of
environmental benzene in urban areas has been implicated in increasing the risk for metabolic
dysfunction across all ages. However, a direct link between exposure to low-dose benzene and
metabolic homeostasis is not yet established. Using the limited available literature on
environmental exposure to benzene and its metabolic outcomes, we performed a preliminary
meta-analysis and found a positive association between exposure to benzene and metabolic
impairments. Our preliminary studies provide strong evidence that chronic exposure to benzene
at varying low doses, modeling human exposure routes, induces significant insulin resistance
and hyperglycemia in rodents. Neuroinflammation is increasingly recognized as one of the causal
factors in the pathology of metabolic diseases. Glial cells (microglia and astrocytes) have recently
garnered specific attention for their role in neuroinflammatory responses in metabolic disorders.
Microglia, produce various pro-inflammatory molecules that are critical for the development of
peripheral metabolic imbalance and insulin resistance via hypothalamic inflammation. We show
that benzene exposure at several low doses relevant to occupational and environmental
exposure promotes robust hypothalamic glial activation and elevation in the hypothalamic
inflammatory IKKβ/NF-κB signaling pathway followed by the induction of endoplasmic reticulum
(ER) stress response. Our central hypothesis is that benzene-induced changes in microglial
function and IKKβ/NF-κB signaling underlie changes in whole-body glucose homeostasis and
metabolic responses. This hypothesis will be assessed with a novel murine model of air-pollution
combining molecular, genetic, and physiological approaches designed to manipulate both the
number and the inflammatory activation state of resident microglia in the following Specific
Aims: 1) To determine the contribution of exposure to low benzene concentrations to
neuroinflammation and metabolic regulation; 2) To determine the role of central IKKβ/NF-κB
inflammatory mechanism in a benzene-induced metabolic imbalance: 3) To determine the cellular
and molecular interplay between microglia neuroinflammation and ER stress response triggered
by benzene exposure. The proposed research will, for the first time, directly assess the role of
benzene-induced changes in glial function and inflammatory signaling in regulating whole-body
metabolism. Such a study will be of importance for shaping public health policy regarding
benzene exposure and its role in predisposition to develop metabolic diseases.
摘要
苯是一种主要的挥发性有机化合物(VOCs),存在于水,食品,油漆,
清洁剂、汽车尾气、烟草烟雾和电子烟蒸汽。接触低剂量
城市地区的环境苯与增加代谢性疾病的风险有关。
所有年龄段的功能障碍。然而,暴露于低剂量苯和
代谢平衡尚未建立。利用有限的可用文献,
环境暴露苯及其代谢结果,我们进行了初步的
荟萃分析发现,苯暴露与代谢之间存在正相关,
损伤我们的初步研究提供了强有力的证据表明长期接触苯
在不同的低剂量下,模拟人体暴露途径,诱导显著的胰岛素抵抗
和高血糖症。神经炎症越来越多地被认为是
代谢性疾病的病理因素。神经胶质细胞(小胶质细胞和星形胶质细胞)最近
因其在代谢紊乱的神经炎症反应中的作用而受到特别关注。
小胶质细胞,产生各种促炎分子,这些分子对发展中国家的疾病至关重要。
外周代谢失衡和胰岛素抵抗通过下丘脑炎症。我们表明
几种低剂量苯暴露与职业和环境有关,
暴露促进下丘脑神经胶质细胞的强烈活化和下丘脑神经胶质细胞的升高
炎症性IKKβ/NF-κB信号通路随后诱导内质网
(ER)应激反应我们的中心假设是苯诱导的小胶质细胞的变化
功能和IKKβ/NF-κB信号转导是全身葡萄糖稳态变化的基础,
代谢反应这一假设将评估与一种新的小鼠模型的空气污染
结合分子,遗传和生理方法,旨在操纵这两个
在以下特定的情况下,常驻小胶质细胞的数量和炎症激活状态
目的:1)确定接触低浓度苯对
研究IKKβ/NF-κB在神经炎症和代谢调节中的作用
苯诱导的代谢失衡中的炎症机制:3)确定细胞
以及小胶质细胞神经炎症和内质网应激反应之间的分子相互作用,
苯暴露。这项拟议的研究将首次直接评估
苯诱导的胶质细胞功能和炎症信号调节全身的变化
新陈代谢.这样的研究将对制定公共卫生政策具有重要意义,
苯暴露及其在易患代谢性疾病中的作用。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Marianna Sadagurski其他文献
Marianna Sadagurski的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Marianna Sadagurski', 18)}}的其他基金
Canagliflozin as a Neuroprotective Agent to Improve Neuroinflammation and Cognitive Function during Aging
卡格列净作为神经保护剂改善衰老过程中的神经炎症和认知功能
- 批准号:
10740151 - 财政年份:2023
- 资助金额:
$ 38.76万 - 项目类别:
Benzene exposure promotes neuroinflammation and metabolic dysregulation
接触苯会促进神经炎症和代谢失调
- 批准号:
10445653 - 财政年份:2022
- 资助金额:
$ 38.76万 - 项目类别:
相似海外基金
Hormone therapy, age of menopause, previous parity, and APOE genotype affect cognition in aging humans.
激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
- 批准号:
495182 - 财政年份:2023
- 资助金额:
$ 38.76万 - 项目类别:
Investigating how alternative splicing processes affect cartilage biology from development to old age
研究选择性剪接过程如何影响从发育到老年的软骨生物学
- 批准号:
2601817 - 财政年份:2021
- 资助金额:
$ 38.76万 - 项目类别:
Studentship
RAPID: Coronavirus Risk Communication: How Age and Communication Format Affect Risk Perception and Behaviors
RAPID:冠状病毒风险沟通:年龄和沟通方式如何影响风险认知和行为
- 批准号:
2029039 - 财政年份:2020
- 资助金额:
$ 38.76万 - 项目类别:
Standard Grant
Neighborhood and Parent Variables Affect Low-Income Preschool Age Child Physical Activity
社区和家长变量影响低收入学龄前儿童的身体活动
- 批准号:
9888417 - 财政年份:2019
- 资助金额:
$ 38.76万 - 项目类别:
The affect of Age related hearing loss for cognitive function
年龄相关性听力损失对认知功能的影响
- 批准号:
17K11318 - 财政年份:2017
- 资助金额:
$ 38.76万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
- 批准号:
9320090 - 财政年份:2017
- 资助金额:
$ 38.76万 - 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
- 批准号:
10166936 - 财政年份:2017
- 资助金额:
$ 38.76万 - 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
- 批准号:
9761593 - 财政年份:2017
- 资助金额:
$ 38.76万 - 项目类别:
How age dependent molecular changes in T follicular helper cells affect their function
滤泡辅助 T 细胞的年龄依赖性分子变化如何影响其功能
- 批准号:
BB/M50306X/1 - 财政年份:2014
- 资助金额:
$ 38.76万 - 项目类别:
Training Grant
Inflamm-aging: What do we know about the effect of inflammation on HIV treatment and disease as we age, and how does this affect our search for a Cure?
炎症衰老:随着年龄的增长,我们对炎症对艾滋病毒治疗和疾病的影响了解多少?这对我们寻找治愈方法有何影响?
- 批准号:
288272 - 财政年份:2013
- 资助金额:
$ 38.76万 - 项目类别:
Miscellaneous Programs